DK2897589T3

DK2897589T3 - Inhalable drug

Info

Publication number: DK2897589T3
Application number: DK14809570.6T
Authority: DK
Inventors: Libo Wu; Mukul Dalvi
Original assignee: Teva Branded Pharmaceutical Prod R & D Inc
Priority date: 2013-11-22
Filing date: 2014-11-21
Publication date: 2018-03-12
Also published as: JP6397025B2; EP2897589B1; US20150190510A1; US9707295B2; HK1212903A1; HK1215395A1; EP2897589A1; JP2016537392A; HUE036748T2; US9364540B2; CN105263473A; TR201802607T4; WO2015077574A1; AU2014352793A1; CA2930170A1; PL2897589T3; MX2016006376A; AU2014352793B2; ZA201603463B; EA201691068A1

Abstract

The present invention provides a solution formulation for inhalation comprising: a liquid phase; an active ingredient containing a carboxylic ester in which the oxygen atom is covalently bound to a quaternary nitrogen-containing heterocycle, dissolved in the liquid phase; and a magnesium or calcium salt, dissolved in the liquid phase. The formulation is particularly suited to pMDIs and nebulisers.

Description

DESCRIPTION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 61/907,778, filed November 22, 2013.

FIELD OF THE INVENTION

[0002] The present invention relates to an inhalable medicament and more specifically to a solution formulation comprising an active ingredient susceptible to chemical degradation.

DISCUSSION OF THE RELATED ART

[0003] A number of active ingredients commonly used in inhalation therapy and in particular in maintenance bronchodilator treatment to relieve symptoms of patients with asthma and chronic obstructive pulmonary disease (COPD) have structures based around quaternary derivatives of atropine. These active ingredients tend to belong to a class of compounds known as antimuscarinic agents, which are compounds that operate on the muscarinic acetylcholine receptors.

[0004] Atropine has the structure:

[0005] Atropine is based around a carboxylic ester in which the oxygen atom is covalently bound to a nitrogen-containing heterocycle. The quaternary derivatives of atropine which have subsequently been developed contain the carboxylic ester in which the oxygen atom is covalently bound to a quaternary nitrogen-containing heterocycle.

[0006] Common examples of active ingredients having this functionality are tiotropium (1), ipratropium (2), glycopyrronium (3), oxitropium (4), aclidinium (5) and trospium (6). The structures of these active ingredients are depicted below, where X' has been added to denote the counterion. c

[0007] Various approaches have been used for formulating inhalable medicaments, including dry powder inhaler (DPI) formulations, pressurised metered dose inhaler (pMDI) formulations and nebuliser formulations. The purpose of an inhalable formulation is to present the formulation in the form of an aerosol of particles having a particle size suitable for lung deposition (typically a mass median aerodynamic diameter (MMAD) of 1-5 microns). In the case of a liquid formulation, aerosolisation forms droplets of drug dissolved or suspended in the droplets, followed by full or partial evaporation of the liquid phase leading to particles having a size suitable for lung deposition (MMAD as above).

[0008] Typically, approaches which use dry powders suffer from the drawback that only a small portion of the powdered active ingredient is actually inhaled into the lungs.

[0009] pMDIs and nebulisers are generally more efficient. pMDI and nebuliser formulations may be presented as suspensions or solutions. In a solution formulation, the active ingredient is dissolved in a liquid phase - a hydrofluoroalkane (HFA) propellant for pMDIs or an aqueous phase for nebulisers.

[0010] Drawbacks associated with suspensions are potential blockage of the pMDI dispensing nozzle orifice, physical instability of the suspended particles and the requirement to use suspending agents such as surfactants. Solution formulations are easier to manufacture and do not suffer from the above-described drawbacks. However, a significant problem associated with formulating active ingredients as a solution formulation is that active ingredients are chemically more reactive in solution than they are in the solid phase. This is a particular problem for active ingredients containing a carboxylic ester in which the oxygen atom is covalently bound to a quaternary nitrogen-containing heterocycle, because they are particularly sensitive to chemical degradation, particularly hydrolysis or solvolysis of the ester leading to de-esterification and/or trans-esterification (by reaction with any alcohols present in the liquid phase, e.g. ethanol).

[0011] Therefore, there remains a need in the art for solution formulations of such active ingredients with increased chemically stability.

[0012] US 2003/149007 relates to a dual bronchodilator inhalation solution, system, kit and method for relieving bronchospasm in patients suffering from chronic obstructive pulmonary disease (COPD). EP2 606 891 relates to a solution formulation comprising a tiotropium salt, 12-20% ethanol, 0.1-1.5% of water, 0.05-0.10% citric acid (or other organic acid) and an HFA propellant, wherein the percentages are percentages by weight based on the total weight of the formulation.

SUMMARY OF THE INVENTION

[0013] Accordingly, the present invention provides a solution formulation for inhalation comprising: a liquid phase; an active ingredient containing a carboxylic ester in which the oxygen atom is covalently bound to a quaternary nitrogen-containing heterocycle, dissolved in the liquid phase; and a magnesium or calcium salt, dissolved in the liquid phase; wherein the amount of salt is from 0.0001 to 0.01 wt%, based on the total weight of the formulation, and wherein the amount of active ingredient is from 0.001-0.4 wt%, based on the total weight of the formulation.

[0014] That is, quaternary derivatives of atropine in solution have been unexpectedly found to be stabilised by dissolved magnesium and calcium salts.

DESCRIPTION OF THE DRAWING

[0015] Figure 1 shows the results of a degradation study using tiotropium bromide.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0016] The present invention will now be described with reference to the accompanying drawing, in which Fig. 1 shows the results of a degradation study using tiotropium bromide.

[0017] The formulation of the present invention contains an active ingredient containing a carboxylic ester in which the oxygen atom is covalently bound to a quaternary nitrogen-containing heterocycle. As previously explained, these active ingredients are conceptually related to atropine, but contain a quaternary nitrogen atom (i.e. a quaternary ammonium cation). The quaternary nitrogen-containing heterocycle is typically saturated. It may be mono-, bi- or tricyclic. The active ingredient may also have a hydroxyl group in the a- or β-position with respect to the ester carbonyl carbon atom, more particularly the a-position.

[0018] Preferably, the active ingredient is selected from tiotropium, ipratropium, glycopyrronium, oxitropium, aclidinium and trospium. More preferably, the active ingredient is a bromide salt of these active ingredients, e.g. tiotropium bromide.

[0019] The amount of the active ingredient present will vary depending on the dose of active ingredient that is required for the particular product, medical indication and patient. The amount of active ingredient is from 0.001-0.4 wt%, based on the total weight of the formulation and preferably 0.005-0.1 wt%, based on the total weight of the formulation.

[0020] The formulation of the present invention also contains a magnesium or calcium salt. This salt is dissolved in the liquid phase and hence is a soluble salt. The formulation provides a homogeneous phase containing, inter alia, the salt. Preferably, the salt is selected from magnesium chloride, magnesium citrate, calcium chloride and calcium citrate (although magnesium citrate is less preferred for HFA formulations because it is harder to dissolve in such formulations), more preferably from magnesium chloride and calcium chloride, and most preferably, the salt is magnesium chloride. The amount of salt is from 0.0001 to 0.01 wt%, based on the total weight of the formulation. Preferably, the amount of salt is from 0.001 to 0.005 wt%, based on the total weight of the formulation. The salt provides the required stability to the active ingredient when in solution.

[0021] The molar ratio of the active ingredient (based on the cation) to salt (based on the magnesium or calcium) is preferably 1:0.5 to 1:3.

[0022] Accordingly, the present invention also provides for the use of a magnesium or calcium salt in a solution formulation for inhalation, for the stabilisation of an active ingredient containing a carboxylic ester in which the oxygen atom is covalently bound to a quaternary nitrogen-containing heterocycle.

[0023] The formulation of the present invention is a solution formulation and hence the active ingredient, the salt and the liquid phase form a single homogeneous phase. The active ingredient and the salt are dissolved in the liquid phase. Therefore, the active ingredient and the salt must be soluble in the liquid phase. Preferably, the formulation can be cooled to 4°C and then re-heated to ambient temperature without precipitation of the active ingredient. The present invention does not preclude other components being present in the formulation including components which are not in solution, e.g. other active ingredients which are present in suspended form.

[0024] The formulation of the present invention described herein may be a pMDI or a nebuliser formulation. That is, the formulations of the present invention can be used in pMDIs and/or nebulisers.

[0025] When the formulation according to the present invention is for a pMDI, the liquid phase comprises an HFA propellant. HFA propellants are well known in the art. The preferred FIFAs of the present invention are FIFA 134a and/or FIFA 227, most preferably FIFA 134a.

[0026] When the formulation according to the present invention is for a pMDI, the liquid phase may additionally comprise a co-solvent. Suitable examples of co-solvents are water, alcohols having 1 to 3 carbon atoms, alkanes having 3 to 6 carbon atoms and dialkyl ethers having 2 to 4 carbon atoms. Specific examples of suitable co-solvents are water, ethanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycerol, propane, butane, isobutane, pentane, dimethyl ether and diethyl ether.

[0027] The co-solvent preferably comprises ethanol, water and/or glycerol. More preferably, the cosolvent comprises ethanol. In a particularly preferred embodiment, the co-solvent comprises ethanol and water. Most preferably, the co-solvent comprises ethanol, water and glycerol.

[0028] When the co-solvent comprises ethanol, the ethanol is preferably dehydrated ethanol. The ethanol is principally present to solubilise the active ingredient. In a preferred embodiment, the amount of ethanol is 5 to 25 wt%, more preferably 10 to 20 wt%, based on the total weight to the formulation.

[0029] When the co-solvent comprises water, the water is preferably water for inhalation. The water is preferably present at 0.1 to 1.0 wt% and more preferably 0.3 to 0.7 wt%, based on the total weight to the formulation.

[0030] When the co-solvent comprises glycerol, the glycerol is present at 0.5 to 2.0 wt%, based on the total weight to the formulation. For some applications, the droplet sizes of the active ingredient dissolved in the liquid phase will be too small for optimal lung deposition. In such cases, glycerol may be added to the formulation. Glycerol is less volatile than most co-solvents used in solution formulations according to the present invention (for example, ethanol) and hence experiences less evaporation on actuation, thereby providing larger droplets (by larger is meant that they have a higher M MAD).

[0031] In a preferred embodiment, the formulation comprises tiotropium bromide, ethanol, glycerol, water, citric acid, magnesium chloride and an HFA propellant.

[0032] On actuation of a pMDI, a metered dose of the formulation is released from the inhaler. The metered dose of the formulation passes through a valve stem and stem block where it is discharged via an orifice in a dispensing nozzle of the stem block into a mouthpiece and hence to the patient. On release, most of the liquid phase rapidly evaporates The particle size of the emitted particles will depend on a number of factors, including the size of the orifice in the dispensing nozzle, the spray force, the plume geometry, the precise amount of co-solvent used (if present), etc. Typically, however, the particles will be less than 5 microns in diameter (MMAD).

[0033] It should be noted that MMADs may be measured using a next-generation impactor (NGI).

[0034] pMDIs are well known in the art; see, for example, Drug Delivery to the Respiratory Tract, Eds. D. Ganderton and T. Jones, VCH Publishers, 1987, pages 87-88, or Pharmaceutics - The Science of Dosage Form Design, Second Edition, Ed. M.E. Aulton, Churchill Livingstone, 2002, page 476 et seq for details.

[0035] pMDIs typically have a medicament-containing canister and an actuator housing having a mouthpiece. The canister is usually formed from an aluminium cup having a crimped lid which carries a metering valve assembly. The metering valve assembly is provided with a protruding valve stem which is inserted as a push fit into the stem block in the actuator housing.

[0036] To actuate, the user applies a compressive force to the closed end of the canister. The internal components of the metering valve assembly are spring loaded so that, typically, a compressive force of 15 to 35 N is required to activate the device. In response to this compressive force, the canister moves axially with respect to the valve stem by an amount varying between about 2 and 4 mm. This degree of axial movement is sufficient to actuate the metering valve and cause a metered quantity of the formulation to be expelled through the valve stem. This is then released into the mouthpiece via an orifice in the dispensing nozzle of the stem block. A user inhaling through the mouthpiece of the device at this point will thus receive a dose of the active ingredient.

[0037] An inhalation-actuated inhaler (also known as breath-actuated inhaler) is particularly preferred in order to prevent inadvertent actuation into the eye(s) of the patient. Suitable inhalers are disclosed in WO 92/09323, GB 2 264 238 and WO 01/93933. When the formulation of the present invention is for a pMDI, the present invention most preferably employs the inhaler as described with reference to Figs. 3-5 of WO 92/09323.

[0038] The present invention further provides a pMDI comprising a canister, wherein the canister contains the solution formulation as described herein. The canister is located in the actuator housing as discussed herein. The canister preferably contains 100 actuations or fewer, preferably about 60 actuations (i.e. a one-month supply, based on two actuations per dose). This is a relatively low quantity and hence the head space in the canister tends to be greater than with conventional pMDIs which provides an increased tendency for the active ingredient to degrade chemically. However, even in this more challenging environment, the formulation of the present invention is able to provide the required level of chemical stability. For example, a 10 ml_ brim-full-capacity canister may have a fill volume of 2.5 to 6.3 mL and a corresponding headspace volume of 7.5 to 3.7 mL. The valve is preferably a 25 to 63 microlitre valve, more preferably a 25 or 50 microlitre valve.

[0039] It has also been found that the formulation of the present invention is not only capable of reducing or preventing chemical degradation of the active ingredient, but also does not significantly affect the material of the canister. This provides the significant advantage that an uncoated aluminium canister may be used, thereby reducing the costs of the pMDI without adversely affecting the formulation. Thus, according to a preferred embodiment of the present invention, the pMDI comprises a canister composed of uncoated aluminium, anodised aluminium (e.g., with hydrofluoric or nitric acid), or aluminium in which the internal surfaces are coated with a fluorinated polymer (e.g., FEP or FCP), more preferably uncoated aluminium.

[0040] When the formulation according to the present invention is for a nebuliser, the liquid phase comprises water. Co-solvents may also be present, as described hereinabove with reference to pMDIs.

[0041] In a nebuliser, the solution is atomised in order to deliver droplets of the active ingredient in the liquid phase. Nebulisers are well known in the art and further details may be found in, for example, Pharmaceutics - The Science of Dosage form Design" Second Edition, Ed. M.E. Aulton, Churchill Livingston, 2002. Nebulisers include soft-mist generating devices, such as Respimat®.

[0042] The formulation of the present invention may additionally comprise citric acid. Citric acid has been found to provide additional stabilisation in the presence of the salts. Preferably, the citric acid is present in 0.01 to 0.2 wt%, based on the total weight of the formulation.

[0043] The present invention further provides a nebuliser comprising a reservoir, wherein the reservoir contains the formulation as described herein.

[0044] As the formulation is a solution, the formulation does not require the presence of surfactants (which are used to stabilise suspended particles of the active ingredient in a suspension formulation). Accordingly, it is not necessary to add surfactant to the formulation and hence the formulation of the present invention is preferably substantially free of surfactant (e.g., the formulation contains less than 0.0001 % by weight of surfactant).

[0045] The present invention will now be described with reference to the following example, which is not intended to be limiting.

Example [0046] Batches of solution formulations were prepared by combining tiotropium bromide, ethanol, water, glycerol and magnesium chloride (invention) or manganese chloride (comparative) and mixing the components until a solution was formed. All formulations contained 0.015 wt% tiotropium bromide and FIFA 134a to 100 wt%. The solution was charged into a canister (as specified in Table 1) which was then sealed with a valve (as specified in Table 1) and filled with HFA 134a. The amounts of the excipients are set out in the Table 1.

Table 1. Formulations for degradation studies

[0047] The results of degradation studies conducted at 50°C are shown in Fig.1. The impurities left to right within each batch are: known impurity A; known impurity B; known impurity TB-iso; known impurity E; known ethyl ester; total known impurities; total unknown impurities; and total known + unknown impurities. The known impurities are: A 2-hydroxy-2,2-dithiophen-2-ylacetic acid; B (1R,2R,4S,5S,7s)-9-methyl-3-oxa-9-azatricyclo[3.3.1,02>4]nonan-7-yl 2-hydroxy-2,2-dithiophen-2-ylacetate; C (1 R,3s,5S)-3-[(2-hydroxy-2,2-dithiophen-2-ylacetyl)oxy]-8,8-dimethyl-8- azoniabicyclo[3,2.1] oct-6-ene bromide; D (1 R,3s,5S)-8-methyl-8-azabicyclo[3.2.1 ]oct-6-en-3-yl2-hydroxy-2,2-dithiophen-2-ylacetate; E methyl 2-hydroxy-2,2-dithiophen-2-ylacetate; F dithiophen-2- ylmethanone; G (1R,2R,4S,5S,7s)-7-hydroxy-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02·4] nonane bromide; FI (1s,3RS,4RS,5RS,7SR)-4-hydroxy-6,6-dimethyl-2-oxa-6-azoniatricyclo [3.3.1,03-7]nonane bromide; I (1R,2R,4S,5S,7r)-7-[(2-hydroxy-2,2-dithiophen-2-ylacetyt)oxy]-9,9-dimethyl-3-oxa-9-

azoniatricyclo[3.3.1.02-4]nonane bromide; J (1R,3s,5S,8s)-8-(chloromethyl)-3-[(2-hydroxy-2,2-dithiophen-2-ylacetyl)oxy]-8-methyl-8-azoniabicyclo[3.2.1] oct-6-ene chloride; and K (1R,2R,4S,5S,7s)-9-acetyl-3-oxa-9-azatricyclo[3.3.1.024]nonan-7-yl 2-hydroxy-2,2-dithiophen-2-ylacetate.

[0048] The results show an acceptably low level of chemical degradation after 6 weeks for batch E.

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description • US619077788 rø001l

• US2003149QQ7A • EP26Q6891A ΓΟΟΙ 21 • WQ9209323A Γ0037Ϊ F00371 • GB2264238A Γ00371 • WOQ193933A jO037]

Non-patent literature cited in the description • Drug Delivery to the Respiratory TractVCH Publishersl 987000087-88 fQQ34| • Pharmaceutics - The Science of Dosage Form DesignChurchill Livingstone20020000476- |O034] • Pharmaceutics - The Science of Dosage form DesignChurchill Livingston20020000 Γ00411

Claims

1. Opløsningsformulering til inhalation omfattende: en flydende fase; en aktiv bestanddel indeholdende en carboxylester, i hvilken oxygenatomet er kovalent bundet til en kvaternær nitrogenholdig heterocyklus, opløst i den flydende fase; et magnesium- eller calciumsalt, opløst i den flydende fase; hvor mængden af salt er fra 0,0001 til 0,01 vægt-%, beregnet på basis af formuleringens samlede vægt, og hvor mængden af aktiv bestanddel er fra 0,001 til 0,4 vægt-%, beregnet på basis af formuleringens samlede vægt.An inhalation solution formulation comprising: a liquid phase; an active ingredient containing a carboxylic ester in which the oxygen atom is covalently linked to a quaternary nitrogen-containing heterocycle dissolved in the liquid phase; a magnesium or calcium salt, dissolved in the liquid phase; wherein the amount of salt is from 0.0001 to 0.01% by weight, based on the total weight of the formulation, and wherein the amount of active ingredient is from 0.001 to 0.4% by weight, based on the total weight of the formulation.

2. Formulering ifølge krav 1, hvor den aktive bestanddel er udvalgt blandt tiotropium, ipratropium, glycopyrronium, oxitropium, aclidinium og trospium, fortrinsvis hvor den aktive bestanddel er tiotropiumbromid.The formulation of claim 1, wherein the active ingredient is selected from tiotropium, ipratropium, glycopyrronium, oxitropium, aclidinium and trospium, preferably wherein the active ingredient is tiotropium bromide.

3. Formulering ifølge et af de foregående krav, hvor mængden af aktiv bestanddel er fra 0,005 til 0,1 vægt-%, beregnet på basis af formuleringens samlede vægt.A formulation according to any one of the preceding claims, wherein the amount of active ingredient is from 0.005 to 0.1% by weight, calculated on the basis of the total weight of the formulation.

4. Formulering ifølge et af de foregående krav, hvor molforholdet mellem den aktive bestanddel (baseret på kationen) og salt (baseret på magnesium eller calcium) er 1:0,5 til 1:3.A formulation according to any one of the preceding claims, wherein the molar ratio of the active ingredient (based on the cation) to salt (based on magnesium or calcium) is 1: 0.5 to 1: 3.

5. Formulering ifølge et af de foregående krav, hvor saltet er udvalgt blandt magnesiumchlorid, magnesiumcitrat, calciumchlorid og calciumcitrat.A formulation according to any one of the preceding claims, wherein the salt is selected from magnesium chloride, magnesium citrate, calcium chloride and calcium citrate.

6. Formulering ifølge et af de foregående krav, hvor formuleringen er til en doseringsinhalator under tryk, og den flydende fase omfatter et FIFA-driv-middel.A formulation according to any one of the preceding claims, wherein the formulation is for a pressurized dosage inhaler and the liquid phase comprises a FIFA propellant.

7. Formulering ifølge krav 6, hvor den flydende fase yderligere omfatter et co-opløsningsmiddel, fortrinsvis hvor co-opløsningsmidlet omfatter ethanol.The formulation of claim 6, wherein the liquid phase further comprises a co-solvent, preferably wherein the co-solvent comprises ethanol.

8. Formulering ifølge krav 7, hvor formuleringen omfatter tiotropiumbromid, ethanol, glycerol, vand, citronsyre, magnesiumchlorid og et HFA-drivmiddel.The formulation of claim 7, wherein the formulation comprises tiotropium bromide, ethanol, glycerol, water, citric acid, magnesium chloride and an HFA propellant.

9. Formulering ifølge et af kravene 1 til 5, hvor formuleringen er til en forstøver, og den flydende fase omfatter vand.A formulation according to any one of claims 1 to 5, wherein the formulation is for a nebulizer and the liquid phase comprises water.

10. Doseringsinhalator omfattende en beholder, hvor beholderen omfatter formuleringen ifølge et af kravene 1 til 8.A dosage inhaler comprising a container, the container comprising the formulation of any one of claims 1 to 8.

11. Doseringsinhalator ifølge krav 10, hvor beholderen er fremstillet af aluminium, i hvilken de indvendige overflader ikke er coatede.The dosage inhaler of claim 10, wherein the container is made of aluminum in which the inner surfaces are not coated.

12. Doseringsinhalator omfattende et reservoir, hvor reservoiret indeholder formuleringen ifølge et af kravene 1 til 5 eller 9.A dosage inhaler comprising a reservoir, wherein the reservoir contains the formulation of any one of claims 1 to 5 or 9.

13. Anvendelse af et magnesium- eller calciumsalt i en opløsningsformulering til inhalation, ifølge et af kravene 1-9, til stabilisering af en aktiv bestanddel indeholdende en carboxylester, i hvilken oxygenatomet er kovalent bundet til en kvaternær nitrogenholdig heterocyklus.Use of a magnesium or calcium salt in a solution formulation for inhalation, according to any one of claims 1-9, for stabilizing an active ingredient containing a carboxylic ester in which the oxygen atom is covalently linked to a quaternary nitrogen-containing heterocycle.